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Research Areas

Intervertebral Disc Regeneration—Making the Intervertebral Disc Young Again


ACL

"My back hurts, doc" is one of the most common complaints heard by family doctors. Low back pain is a huge medical challenge, mostly caused by degeneration of the intervertebral disc. Unfortunately, no cure for disc degeneration has been found yet. The Sheyn Lab is working on developing new therapies that will benefit patients not only by improving their quality of life, but also by reducing medical costs and missed workdays. Specifically, the lab aims to reverse the degenerative process and rejuvenate the disc through development of an induced pluripotent stem cell-mediated therapy. We are investigating the stem cell-mediated therapy in multiple preclinical models: in organ cultures, small and large animals (Figure 1). Further research will determine the safety, efficacy and mode of function of this potential therapy. This study was funded by the California Institute for Regenerative Medicine and NIH/NIAMS.

Figure 1. Model of disc degeneration in a large animal. A: Porcine IVD organ culture B: µMRI image of porcine IVD organ culture. Macrograph of healthy porcine IVD. C: Histology and standard H&E staining of porcine IVD. D: Transformation of iPS cells towards notochordal cells in vitro. Loss of pluripotent stem cell markers and rise of mesodermal markers expression in vitro (adopted from: Sheyn, et al., Theranostics, 2019).

Challenging Dogmas and Developing New Treatments in Sports Medicine


ACL

The worldwide estimation of young sports players that require surgery following a knee injury lies between 17–61%. The anterior cruciate ligament (ACL), a main stabilizing structure of the knee, is one of the most commonly injured ligaments. Annual costs are about $6 billion. The healing potential of the ACL is reported to be extremely poor. About 40-50% of partially torn ACL progress to complete ligament deficiencies and tears. These ACL lesions are considered potentially complete tear. At present, treatments for complete and potentially complete ACL tears include mainly reconstruction using autografts and allografts, with disadvantages, such as pain for the patient, a high risk to develop osteoarthritis as well as limited long-term function. Our lab is interested in development stem cell therapies that will be able to fill the gap in the regeneration needs of soft tissues and provide a minimally invasive solution for such injuries and prevent osteoarthritis caused by injuries in the knee and other joints. For that purpose, we are aiming to develop an anti-inflammatory, injectable stem cell therapy using large animal porcine model (Figure 2A-C).

The meniscus is at the cornerstone of knee joint function, imparting stability and ensuring shock absorption, load transmission and stress distribution within the knee joint. However, it is very vulnerable to injury and age-related degeneration. Knee osteoarthritis progresses more rapidly in the absence of a functional meniscus. Historically, tears extending to the avascular inner portion of the meniscus (white-white zone, "WW"), such as radial tears were considered as untreatable and were often resected, due to the lack of vascularity in the WW zone. Perfusion-based anatomical studies performed on cadaveric menisci in the 1980s shaped the current dogma that human meniscus has poor regenerative capacity, partly due to limited blood supply that only reaches 10-25% of the meniscus, commonly referred to as red-red zone ("RR"). We hypothesize that the "avascular" white-white zone of the meniscus possesses regenerative capacity due to microvasculature and a resident stem/progenitor cell population. We investigate the occurrence of micro-vessels and progenitors in different zones using optical clearing and 3D imaging (Figure 2E-H).

Figure 2. Post-traumatic osteoarthritis prevention using mesenchymal stem cells implanted in the knee joint, large animal model (A-C). A: Cell injection to porcine knee under fluoroscopic guidance. B: Cell detected using fluorescent imaging. C: Cell detected using bioluminescent imaging. D: Cell detected using MRI. Studying the vascularization and resident stem cell populations in human meniscus using optical clearing technique (D-F). E: Schematic representation of different zones of the meniscus. F: Human meniscus before processing. G: Segment of human meniscus that was cleared using modified uDisco protocol. H: 3D fluorescent imaging of cells and blood vessels in cleared meniscus.

Revitalization of Allografts—Bringing New Life to Dead Bone Grafts for Craniofacial Injuries


Cranial bone loss due to trauma and tumor resection presents a major clinical challenge, affecting over 100,000 Americans annually. Bone allografts from tissue donors are typically used to repair such defects. However, allografts are non-viable tissue. Therefore, healing occurs at an extremely slow rate. In the Sheyn lab, we are developing cranial-specific stem cells to efficiently regenerate and revitalize cranial allograft. Therefore, induced pluripotent stem cells are differentiated to neural crest cells, which are the embryonic progenitors that give rise to the bigger parts of the cranial skeleton. In a next step, we differentiate those cells towards adult stem cells to efficiently repopulate structural cranial allograft and to improve healing of the skull (Figure 3).

Figure 3. Bone regeneration using stem cells and parathyroid hormone (PTH). Calvarial allograft repaired with decellularized allografts or allografts seeded with induced pluripotent stem cell-derived neural crest cells that were pre-labeled with Luciferase reporter gene (A) and monitored using µCT image analysis for 8 weeks (B).

Contact the Sheyn Lab

127 S. San Vicente Blvd.
Advanced Health Sciences Pavilion, A8308
Los Angeles, CA 90048